The relationships among nitric oxide production, bacterial translocation, and intestinal injury after endotoxin challenge in vivo.
BACKGROUND
This study examines the hypothesis that there is a relationship among endotoxin-induced bacterial translocation (BT) and increased nitric oxide (NO) production and that inhibition of excessive NO production with NG-monomethyl-L-arginine (L-NMMA) is beneficial.


METHODS
Rats received 0, 1, or 4 mg/kg endotoxin intraperitoneally, and 6 or 18 hours later, they were killed and BT, NO production (as reflected in nitrite/nitrate levels), and calcium-dependent nitric oxide synthase and calcium-independent nitric oxide synthase (iNOS) activities were measured in tissues (ileum, liver, and mesenteric lymph nodes) and blood. In a second set of experiments, the animals received the NOS inhibitor L-NMMA (100 mg/kg) intravenously either 15 minutes before or 2 hours after endotoxin challenge (4 mg/kg) and the same parameters were measured.


RESULTS
The incidence of BT was higher in rats receiving 4 mg/kg endotoxin (62.5%) than in the control group (0%, p < 0.05), and the 1 mg/kg endotoxin group had intermediate incidence (25%). The animals receiving 4 mg/kg endotoxin had higher tissue (mesenteric lymph nodes, liver) and blood nitrite/nitrate levels than the control or 1 mg/kg endotoxin groups. The increased NO production was mainly attributable to an elevated level of iNOS activity. The administration of L-NMMA before but not after endotoxin challenge reduced iNOS activity, NO production, and BT to control levels at 6 hours but not 18 hours after endotoxin administration.


CONCLUSIONS
Endotoxin-induced mucosal injury and BT are associated with iNOS activity and increased NO production. Inhibition of iNOS activity with L-NMMA before treatment prevented endotoxin-induced ileal mucosal injury and BT.
Mishima
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Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark 07103-2714, USA.
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D000818:Animals; D018988:Bacterial Translocation / Q000276:immunology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007413:Intestinal Mucosa / Q000276:immunology / Q000293:injuries* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine / Q000494:pharmacology
D008070:Lipopolysaccharides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase